1. Field of the Invention
The invention relates generally to modification of neurodegenerative protein aggregations associated with neuronal disease.
2. Background Information
In an aging population there is an increasing incidence of neurodegenerative diseases. These diseases that waste the mental faculties while still leaving the physical capabilities substantially intact are an emotional drain on those related to the patient and a major financial drain on the patient, patient families and societies. Many of these diseases have certain common features. One of the features is the formation of pathological conformations of proteins that can lead to protofibrils, fibrils and amorphous aggregations resulting in neuronal cell death.
Among the diseases associated with such etiology are Alzheimer's disease, Parkinson's disease, transmissible spongiform encephalopathies, such as Creutzfeld-Jakob disease, polyglutamine diseases, Huntington disease, and Lou Gehrig's disease, as well as other neuropathologies. Efforts to treat these diseases have been substantially unavailing. The efforts have been impeded by the inability to diagnose the diseases at their early stages and recognizing the existence of the disease until the patient becomes symptomatic. Also, there are the problems of the blood brain barrier, the identification of effective drugs and the incidence of side effects of attempted treatments.
Originally, assay methods were developed that relied on cells in culture, which have provided insights into the etiology of these diseases. The effect of various treatments on neuronal mortality has aided in understanding how one may reduce the level of neuronal toxicity of the aggregates. Today, there are mouse models, where the mice have been genetically modified to represent the neuronal pathologies. In this way, experiments can be performed that more readily approximate the human condition.
The Kiessling laboratory, as well as the Lee and Kung laboratories, among others, have done extensive studies on methods of interfering with protein aggregation in amyloid related diseases, e.g. Alzheimer's disease. The Kiessling group has identified an amino acid sequence in A that appears to be a domain involved with aggregation, amino acids 16-20 (KLVFF)(SEQ ID NO:1). Further efforts are needed to provide compounds that can be used in research to elucidate the mechanisms of the neuropathies, the role played by the formation of fibrils and plaques and the effect of interference of such formation. In this way, compounds can be developed that will be used in the treatment of the neuropathies.
Besides the neuropathies associated with aggregation, other diseases may also involve aggregation, where there is an interest in preventing or deterring the aggregation from inducing a diseased state. In addition, there are other situations where the inhibition of aggregate formation, such as in the analysis of naturally occurring mixtures are of interest.
Relevant Literature
Work by the Kiessling group may be found in Ghanta, et al., 1996 J Biol Chem 271, 29525-28; Lowe, et al., 2001 Biochemistry 40, 7882-89 and Cairo, et al., 2002 Biochemistry 41, 8620-9, describing the binding domain of Aβ and assay methodology. Other articles related to Aβ include Korth, et al., 2001 PNAS 98, 9836-41, Hardy and Selkoe 2002 Science 297, 353-6; Lee, 2002 Neurobiology of Aging 23, 1039-42 and Kim and Lee, 2003, Biochem Biophys Res Comm 303, 576-9, where the latter reports that fullerene has an aggregation inhibiting effect on Aβ. Description of the prolyl isomerase Pin 1 and its role with phosphorylated tau is described in Lu, et al., 1999 Nature 399, 739-40; and Lu, et al., 1999 Nature, 399.
Review articles of protein aggregation associated neuropathies include Zoghbi and Orr, 2000 Ann Rev Neurosci 23, 217-47 (glutamine repeats); Lee, et al., 2000 Ann Rev Neurosci 24, 1121-59; Goedert 2001 Nature Reviews/Neuroscience 2, 482-501 (α-synuclein); Sacchettini, J. C. and Kelly, J. W. (2002) Nature Rev. Drug Discovery 1:267-275—a good recent review of inhibitor strategies; Volles, M. J. and Lansbury, P. T. Jr (2003) Biochemistry 42:7871-7878.—discussion of the latest models of Parkinson's pathology; Koo, E. H. et al (1999) Proc. Natl. Acad. Sci. USA 96:9989-9990—one of the most commonly cited reviews on the subject of amyloid diseases; Kayed, R. et al (2003) Science 300:486-489.—suggests that various amyloidogenic peptides display a common mechanism(s) of aggregation; and Serpell, L. C. (2000) Biochimica et Biophysica Acta 1502:16-30—discusses current thinking about the structure of Aβ aggregates.
Other references of interest include references associated with the experimental procedures: Gordon, D. J. and Meredith, S. C. (2003) Biochemistry 42:475-485; and Graef, I. A. et al 1999 Nature 401:1703-1708 and other references associated with inhibitors: Gordon, D. J. and Meredith, S. C. (2003) Biochemistry 42:475-485—inhibitor peptides; Kim, Y-S. et al (2003) J. Biol. Chem. 278:10842-10850—data shows that Congo red binds to unfolded Aβ peptide; Hammarstrom, P. et al (2003) Science 299:713-716.—inhibitors based on kinetics; Klettner and Henlegen (2003) Curr Drug Target CNS Neurol Disord 2, 152-62—FK506 for treatment of neurological disorders; and Klunk, W. E. et al (1998) Life Sciences 63:1807-1814—first chrysamine G paper.
Spencer, et al., 1983 Science 262, 1019-24 describes the construction of small molecules that are dimeric and bind two different proteins created by DNA recombination. See also, U.S. Pat. Nos. 5,830,462; 6,011,018 and 6,316,418. Briesewitz, et al., 1999 PNAS USA 96, 1953-8 and U.S. Pat. No. 6,372,712 describe the use of an endogenous protein to modulate the affinity of a small molecule.